PROJECT SUMMARY To date, there is no effective treatment to stall or reverse late life cognitive decline. Therefore, prevention, through modification of risk factors, is an essential strategy. In particular, cardiovascular (CV) risk factors in midlife are recognized to influence later-life cognitive status, and results from SPRINT-MIND, FINGER, and related studies suggest that modifying CV risk factors such as blood pressure (BP) in older adults may be a promising avenue to lower risk of late life cognitive decline. However, while CV risk factor modification might be effective on average, at a group level, the cognitive benefits of such modification are highly variable from person to person, with some individuals receiving little benefit despite effective CV risk factor management. Such inter-individual variability could plausibly be influenced by CV risk factors early in life?an under-studied phenomenon. In the previous funding period for R01AG041200, CV, cognitive and physical performance data were collected among 1,298 black and white (35%/65%) Bogalusa Heart Study (BHS) participants who had prospective measurements of growth, adiposity, BP, lipids, insulin resistance (IR) and behavioral factors such as physical activity, diet, alcohol and tobacco use for ?45 years since childhood (average age of 9 years at first exam). We found that childhood and adolescent anthropometric, lipid, BP and IR trajectories provided unique predictive information about mid-life CV risk, cognitive and physical performance, and mediation analyses were used to disentangle some of these causal pathways. Our work over the previous funding period yielded >40 peer-reviewed manuscripts. In the proposed renewal, which would serve as the primary support for continuing in-clinic examination of BHS participants, our cohort is entering their sixth decade of life, and many have worsening CV and metabolic risk factors. They are entering the stage of life at which sub- clinical brain injury (white matter lesions, brain atrophy, and cerebral amyloidosis) first begins to emerge. We will capitalize on this critical life transition period by adding innovative imaging of sub-clinical brain injury, while further characterizing trajectories of CV risk, cognition, and physical function. Together, this data will allow us to answer new questions about the time course of early sub-clinical brain injury while continuing to characterize the impact of early-life influences on cognitive aging. Although clinically significant cognitive impairment is rare at this age, measurements in this epoch establish the trajectory of stable pre-decline cognitive functioning, necessary to identify the earliest departures toward decline. These measures, as well as measures of the earliest adverse brain changes that culminate in dementia, have implications for prevention. Therefore, the proposed next cycle of this study provides a unique and arguably the only opportunity to understand lifespan CV factors associated with healthy brain aging which is only now possible because of the long-term investment made in the BHS cohort. The impact of this work will be to inform, appropriately time, and target intervention opportunities to maintain brain health throughout the aging process.